Nc,NG-dimethyl-L-argmme (ADMA) IS an endogenously synthesized mtnc oxide (NO) synthase mhibltor which has potent pressor/vasoconstnctor effects Dimethylargmmase metabolizes ADMA to L-citrullme and plays a key role m deterrmmng the m VIVO levels of ADMA To mvestlgate the role of ADMA m the pathogenesls of hypertension, we measured 24-hour urinary excretion of ADMA (UADMA) and nitrate/nitrite (NOx) m Dahl salt-sensitive hypertensive rats and spontaneously hypertensive rats (SHR) In Dahl salt-resistant rats, high-salt &et (8% NaCI) did not increase blood pressure and increased urinary NOx (P< 01) wlthout changes in UADMA cornpaled with lowsalt diet (0 3% NaCI) In contrast, m Dahl salt-sensitive rats, hlghsalt diet Increased blood pressure (P< Ol), did not change urinary NOx excretion, and Increased UADMA (P< 01) There was a slgmficant (Y= 65, P< 01) correlation between UADMA and the level of blood pressure m Dahl salt-sensltlve rats Plasma levels of NOx and ADMA and renal chmethylargmmase content were comparable among them These results may suggest that m Dahl salt-resistant rats, blood pressure 1s kept constant during high-salt intake, possibly due to the compensatory increased production of NO, and that m Dahl salt-sensitive rats, high-salt intake increases the production of ADMA, attenuates the compensatory Increase\ m NO, and increases blood pressure These results also suggest that the systemic production of ADMA 19 not dependent on renal dlmethylargmmase SHR had significantly greater urinary NOx excretion (P< 05) and smaller UADMA than Wlstar-Kyoto rats nously have suggested that the NO production 1s preserved m SHR * Furthermore, recent evidence demonstrated the increased but not decreased production of NO m the heart9.10 and aorta" of SHR The synthesis of NO can be inhibited experimentally by some analogues of argmme mcludmg L-NMMA and ADMA), both of which have equally potent vasoconstnctor and pressor actions 12 Acute admmlstratlon of ADMA into guinea pigsI and rats'4 causes blood pressure elevation partly via elevation of total peripheral resistance I4 In humans, mtra-arterial admmlstratlon of ADMA lowers forearm blood flow 1~15 Although both L-NMMA and ADMA are synthesized I6 and metabolized I7 endogenously, the plasma concentration of dlmethylargmme 1s ten times greater than that of L-NMMA 13 Since studies m ammals suggest that the kidney may be mvolved m the excretion lx and metabolism 1Y.*O of ADMA, abnormalities of the ADMA production or ehmmatlon have been reported m human kidney diseases 13 21 Although recent evidence demonstrated high accumulation of ADMA m plasma from hypercholesterolexmc ammals**J3 and m balloon-injured vessels,*4 the role of this endogenous NO synthase mhlbltor m the pathogenesls of hypertension has not been elucidated at all Accordmgly, we hypothesized that endogenous ADMA may play a role m salt-sensitive hypertension by competltlve inhibition of NO synthesis. To test this hypothesis, urinary and plasma ADMA and NOx were evaluated m Dahl rats on different salt intakes....

The changing relationship between stimuli and responses after prolonged receptor stimulation is a general feature of hormonal signaling systems, termed desensitization. This phenomenon has been best exemplified in the covalent modification of the G protein-linked catecholamine receptors. However, other components within this signaling pathway can be involved in desensitization. Here we present evidence that desensitization occurs at the level of the effector enzyme itself through phosphorylation. Type V adenylyl cyclase (AC) is the major isoform expressed in the heart. Using purified enzymes, we demonstrate that protein kinase A (PKA) directly phosphorylates and thereby inhibits type V AC catalytic activity. This inhibition was negated in the presence of PKA inhibitor. Analysis of enzyme kinetics revealed that this inhibition was due to a decrease in the catalytic rate, not to a decrease in the affinity for the substrate ATP. Our results indicate that AC catalytic activity can be regulated through PKA-mediated phosphorylation, suggesting another mechanism of desensitization for receptor pathways which signal via increases in intracellular cAMP.

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